Use of an allogeneic stem cell transplant (allo-SCT) as a therapeutic option for otherwise lethal diseases is continuously increasing. However, graft-versus-host disease (GVHD) remains a major complication of allo-SCT, affecting up to about 40-60% of allo-SCT patients. It is believed that GVHD occurs when immune competent cells, namely, T-lymphocytes, recognize membrane antigens on the host cells. These membrane antigens include a set of host polypeptides such as major and minor histocompatibility antigens displayed by the human leukocyte antigen system. The polymorphism of these polypeptides is believed to trigger T-cell activation and ultimately tissue injury through a variety of cellular effector mechanisms. The activation of the donor immune cells is augmented also by cytokines released from the site of tissue injury associated with the intense conditioning regimen (“cytokine storm”).
Acute GVHD (aGVHD) usually occurs in the first 100 days after transplantation, whereas onset of chronic GVHD (cGVHD) is observed later. Changes in the onset period of both acute and chronic GVHDs have been observed, with acute cases occurring about 100 days after transplantation and chronic cases noticed earlier than usual. These changes from traditional patterns of acute and chronic GVHD were observed especially in the context of reduced conditioning intensity and use of peripheral blood as a stem cell source. As used herein, the term “GVHD” encompasses both acute and chronic graft-versus-host-disease.
The goal of hematopoietic progenitor cell or stem cell transplantation (HSCT) is to achieve the successful engraftment of donor cells within a recipient host, such that immune and/or hematopoietic chimerism results. Such transplants typically are used in the treatment of disorders such as leukemia, bone marrow failure syndromes, and inherited disorders (e.g., sickle cell anemia, thalassemia, immunodeficiency disorders, and metabolic storage diseases such as mucopolysaccharidosis), as well as low-grade lymphoma. Chimerism is the reconstitution of the various compartments of the recipient's hematoimmune system with donor cell populations bearing major histocompatibility complex (MHC) molecules derived from an allogeneic or xenogeneic donor, and a cell population derived from the recipient or, alternatively, the recipient's hematoimmune system compartments which can be reconstituted with a cell population bearing MHC molecules derived from only the allogeneic or xenogeneic marrow donor. Chimerism may vary from 100% (total replacement by allogenic or xenogeneic cells) to low levels detectable only by molecular methods. Chimerism levels may vary over time and be permanent or “temporary”.
Donor leukocyte infusion's (DLI) have been used after allotransplant to treat relapsed or residual disease, to convert mixed to full donor chimerism, to restore full immune function as an ‘add-back’ after T-cell-depleted transplants and as a prophylaxis against relapse as preemptive therapy. The major complications after DLI include acute and chronic GVHD and infections associated with marrow aplasia or the use of immunosuppression. In most trials, up to about 60% of evaluable recipients of DLI develop GVHD. GVHD correlates with GVT activity and response in some but not all studies.
Over the years, several methods for GVHD prophylaxis and treatment have been proposed, such as immunosuppressive medications, graft engineering, and cellular therapies. Indeed, there exist several approaches to minimizing GVHD after DLI to prevent or mitigate post-transplant immune deficiency or to induce graft-versus-malignancy (GVM) in residual or recurring disease. For example, one approach that appears to minimize GVHD involves administration of low-dose DLI followed by dose escalation. The conventional approach to DLI has been to infuse single “bulk” doses containing variable numbers of CD3+ T cells, but this is believed to be associated with significant incidences of acute and chronic GVHD and occasionally with death. On the other hand, transfusion of donor lymphocytes in multiple aliquots, starting at low cell numbers and escalating the dosage at variable intervals as required may reduce the incidence of GVHD. (see Mackinnon S, Papadopoulos E B, Carabasi M H, et al. Adoptive immunotherapy evaluating escalating doses of donor leukocytes for relapse of chronic myeloid leukemia after bone marrow transplantation: separation of graft-versus-leukemia responses from graft-versus-host disease. Blood. 1995; 86:1261-1268). The assumption underlying the use of an escalating dose regimen is that the incidence of GVHD increases with the total cell dose administered. Thus, it is believed that identification of the minimal cell dose capable of inducing remission would reduce the risk for GVHD.
Alternatively, it is believed that GVHD may be reduced through depletion of CD8+ lymphocytes, which are thought to include most of the cells responsible for mediating GVHD (i.e. depletion of GVH effector cells). Outcomes suggest that graft-versus-leukemia activity can be retained with minimal GVHD. In small numbers of patients, the majority of responses have been sustained, although the overall clinical impact of this approach will require direct comparison to unmanipulated DLI.
It is also believed that GVHD may be reduced through inactivation of GVHD effector cells. Indeed, irradiated donor T-cell DLI is based on the hypothesis that the cells would induce GVM effects at the time of infusion but could not proliferate in response to allo-antigens. In addition, the use of donor T-cells expressing the herpes simplex thymidine kinase gene followed by ganciclovir treatment was studied for its effects pertaining to the modulation of alloreactivity occurring after bone marrow transplantation.
Calcineurin inhibitors and methotrexate (MTX) combination therapy has been used successfully to reduce the incidence and severity of GVHD and is the standard of care for GVHD prophylaxis. MTX, one of the earliest drugs used for GVHD prophylaxis, is believed to inhibit dihydrofolate reductase and production of thymidylate and purines, thereby suppressing T-cell response and proliferation as well as expression of adhesion molecules.
Although some of these strategies are effective in reducing the incidence of GVHD, these strategies often associate with a significant reduction in the GVM effect, thus jeopardizing the overall efficacy of HSCT.